Imperial College London

ProfessorSimakAli

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

154 results found

Buluwela L, Kamalati T, Photiou A, Heathcote DA, Jones MD, Ali Set al., 2010, A Simple Laboratory Practical to Illustrate RNA Mediated Gene Interference Using Drosophila Cell Culture, BIOCHEMISTRY AND MOLECULAR BIOLOGY EDUCATION, Vol: 38, Pages: 393-399, ISSN: 1470-8175

Journal article

Ali S, Buluwela L, Coombes RC, Antiestrogens and their therapeutic applications in breast cancer and other diseases, Annu Rev Med, Vol: 62, Pages: 217-232

The identification of the link between breast cancer and estrogens has led to the development of antiestrogens, in particular tamoxifen, to inhibit the activities of estrogen receptors (ERs) in breast cancer cells. The clinical use of tamoxifen has played a major part in decreasing breast cancer mortality over the past 30 years. Though antiestrogenic in the breast, some antiestrogens have estrogen-like actions in other tissues, acting to promote bone density and protect against cardiovascular disease, thus raising the possibility of their use in counteracting the effects of estrogen loss following menopause. Moreover, antiestrogens show efficacy as chemopreventive agents in women at high risk of developing breast cancer. Thus, antiestrogens define an important and well-understood class of cancer drug, which continue to be a mainstay in breast cancer treatment.

Journal article

Thiruchelvam PTR, Hua H, Lai CF, Photiou A, Kyle F, Coombes C, Buluwela L, Ali Set al., 2010, Characterization of estrogen responses in breast cancer cell lines highlights ER alpha as an LRH-1 regulated gene, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Heathcote DA, Patel H, Kroll SH, Hazel P, Periyasamy M, Alikian M, Kannegnti SK, Jogalekar AS, Scheiper B, Barbazanges M, Blum A, Brackow J, Siwicka A, Pace RD, Fuchter MJ, Snyder JP, Liotta DC, Freemont PS, Aboagye EO, Coombes RC, Barrett AG, Ali Set al., 2010, A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration, J Med Chem, Vol: 53, Pages: 8508-8522

Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

Journal article

heathcote D, 2010, A Novel Pyrazolo[1,5-a]pyrimidine Is a Potent Inhibitor of Cyclin-Dependent Protein Kinases 1, 2, and 9, Which Demonstrates Antitumor Effects in Human Tumor Xenografts Following Oral Administration., J. Med. Chem.

Journal article

JOGALEKAR ASHUTOSH S, SNYDER JAMES P, LIOTTA DENNIS C, BARRETT ANTHONY G M, COOMBES RCDS, ALI SIMAK, SIWICKA ALEKSANDRA, BRACKOW JAN, SCHEIPER BODOet al., 2009, Selective Inhibitors for Cyclin-Dependent Kinases

This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.

Journal article

WORTHAM NC, AHAMED E, NICHOL SM, THOMAS RS, PARIVASAMY M, JIANG J, OCHOCKA AM, SHOUSHA S, HUSON LW, BRAY SE, COOMBES RC, ALI S, FULLER-PACE FVet al., 2009, The DEAD-box protein p72 regulates ERα-/oestrogen-dependent transcription and cell growth, and is associated with improved survival in ERα-positive breast cancer, Oncogene, Vol: 28, Pages: 4053-4064, ISSN: 1476-5594

The DEAD-box RNA helicases p68 (DDX5) and p72 (DDX17) have been shown to act as transcriptional co-activators for a diverse range of transcription factors, including oestrogen receptor-α (ERα). Here, we show that, although both proteins interact with and co-activate ERα in reporter gene assays, small interfering RNA-mediated knockdown of p72, but not p68, results in a significant inhibition of oestrogen-dependent transcription of endogenous ERα-responsive genes and oestrogen-dependent growth of MCF-7 and ZR75-1 breast cancer cells. Furthermore, immunohistochemical staining of ERα-positive primary breast cancers for p68 and p72 indicate that p72 expression is associated with an increased period of relapse-free and overall survival (P=0.006 and 0.016, respectively), as well as being inversely associated with Her2 expression (P=0.008). Conversely, p68 shows no association with relapse-free period, or overall survival, but it is associated with an increased expression of Her2 (P=0.001), AIB-1 (P<0.001) and higher tumour grade (P=0.044). Our data thus highlight a crucial role for p72 in ERα co-activation and oestrogen-dependent cell growth and provide evidence in support of distinct but important roles for both p68 and p72 in regulating ERα activity in breast cancer.

Journal article

Ali S, Heathcote DA, Kroll SHB, Jogalekar AS, Scheiper B, Patel H, Brackow J, Siwicka A, Fuchter MJ, Periyasamy M, Tolhurst RS, Kanneganti SK, Snyder JP, Liotta DC, Aboagye EO, Barrett AGM, Coombes RCet al., 2009, The Development of a Selective Cyclin-Dependent Kinase Inhibitor That Shows Antitumor Activity, CANCER RESEARCH, Vol: 69, Pages: 6208-6215, ISSN: 0008-5472

Journal article

BULUWELA LAKI, WAXMAN JONATHAN, ALI SIMAK, NGAN SARAHet al., 2009, METHODS OF AIDING IN THE DIAGNOSIS OF PROSTATE CANCER

The current invention provides a method for aiding in the assessment of prostate cancer (including metastatic prostate cancer) and/or benign prostate hyperplasia in a patient, wherein the method comprises the step of determining the level of Glycine N- methyltransferase (GNMT) nucleic acid and/or protein in a sample from the patient. The invention also provides compounds that target Glycine N-methyltransferase (GNMT) protein and/or nucleic acid for use in treating prostate cancer. Also provided are screening methods for selecting a compound considered to be useful in treating prostate cancer, comprising the steps of determining the ability of a test compound to reduce GNMT activity and selecting a compound that reduces GNMT activity. The invention also provides methods for aiding in the diagnosis of prostate cancer in a patient comprising obtaining a sample from the patient and assessing said sample for a marker of GNMT activity.

Journal article

BULUWELA LAKI, WAXMAN JONATHAN, ALI SIMAK, NGAN SARAHet al., 2009, METHODS OF AIDING IN THE DIAGNOSIS OF PROSTATE CANCER

The current invention provides a method for aiding in the assessment of prostate cancer (including metastatic prostate cancer) and/or benign prostate hyperplasia in a patient, wherein the method comprises the step of determining the level of Glycine N-methyltransferase (GNMT) nucleic acid and/or protein in a sample from the patient. The invention also provides compounds that target Glycine N-methyltransferase (GNMT) protein and/or nucleic acid for use in treating prostate cancer. Also provided are screening methods for selecting a compound considered to be useful in treating prostate cancer, comprising the steps of determining the ability of a test compound to reduce GNMT activity and selecting a compound that reduces GNMT activity. The invention also provides methods for aiding in the diagnosis of prostate cancer in a patient comprising obtaining a sample from the patient and assessing said sample for a marker of GNMT activity.

Journal article

Ngan S, Stronach EA, Photiou A, Waxman J, Ali S, Buluwela Let al., 2009, Microarray coupled to quantitative RT-PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells, ONCOGENE, Vol: 28, Pages: 2051-2063, ISSN: 0950-9232

Journal article

Periyasamy M, Thomas R, Tolhurst R, Ochocka AM, Buluwela L, Ali Set al., 2009, Investigation of the regulation of DNA methylation by the estrogen receptor, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472

Journal article

Thiruchelvam P, Photiou A, Fui LC, Coombes C, Ali S, Buluwela Let al., 2009, Characterization of the nuclear receptor LRH-1 reveals a new form that can function in estrogen regulated breast cancer cell growth, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472

Journal article

Coombes R, Cheiper, Jogalekar AS, Brackow J, Ali S, Heathcote D, Kroll S, Bodo S, Siwicka A, Periyasamy M, Tolhurst R, Kanneganti S, Snyder J, Liotta D, Aboagye E, Barrett Aet al., 2009, The development of a selective CDK7 inhibitor with anti-tumor activity, CANCER RESEARCH, Vol: 69, ISSN: 0008-5472

Journal article

Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JSet al., 2009, Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen (Nature (2008) 456, (663-666)), Nature, Vol: 457, ISSN: 0028-0836

Journal article

Ali S, 2009, Transcriptional coactivators and corepressors in endocrine response and resistance in breast cancer, Therapeutic Resistance to Anti-Hormonal Drugs in Breast Cancer: New Molecular Aspects and their Potential as Targets, Pages: 27-38, ISBN: 9781402085253

Regulation of gene expression by sequence-specific DNA binding proteins involves the co-ordinated action of a repertoire of transcriptional coregulator complexes, which together act to modify chromatin at gene promoters, thereby facilitating gene expression. The mechanisms by which such coregulators are recruited to the promoters of estrogen-responsive genes by estrogen receptor-\upalpha have been well studied in breast cancer cells. These studies have highlighted coactivator and corepressor proteins that appear to be critical for the agonist and antagonist actions of estrogen and anti-estrogens, and indicate that altered levels and/or activities of these proteins is an important feature of response and resistance to endocrine treatments in breast cancer. © Springer Science+Business Media B.V. 2009.

Book chapter

Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson IR, Brown M, Jiang J, Howat WJ, Ali S, Carroll JSet al., 2011, Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen, Nature, Vol: 456, Pages: 663-666

Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response, yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product (PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti-cancer drug tamoxifen. We show that PAX2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2-positive tumours can originate from ER-positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.

Journal article

Fuller-Pace FV, Ali S, 2008, The DEAD box RNA helicases p68 (Ddx5) and p72 (Ddx17): novel transcriptional co-regulators, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 36, Pages: 609-612, ISSN: 0300-5127

Journal article

ALI SIMAK, BULUWELA LAKI, WAXMAN JONATHAN, NGAN SARAHet al., 2008, METHODS OF AIDING IN THE DIAGNOSIS OF PROSTATE CANCER

A method for aiding in the assessment of prostate cancer (including metastatic prostate cancer) and/or benign prostate hyperplasia in a patient, the method comprising the step of determining the level of CNP nucleic acid and/or protein in a sample from the patient. The patient may be at risk of developing prostate cancer, or have already been diagnosed with prostate cancer, or may have undergone treatment for prostate cancer. The method may be for assessing the likely progression of prostate cancer in the patient, or for assessing prostate function, or for assessing and/or predicting the development of prostate cancer. The method may be for diagnosing prostate cancer in the patient or for assessing the response of the patient to treatment for prostate cancer.

Journal article

SCHEIPER BODO, SNYDER JAMES P, BARRETT ANTHONY G M, ALI SIMAK, LIOTTA DENNIS C, BRACKOW JAN, JOGALEKAR ASHUTOSH S, SIWICKA ALEKSANDRA, COOMBES RCDSet al., 2008, SELECTIVE INHIBITORS FOR CYCLIN-DEPENDENT KINASES

This invention provides a class of compounds which are useful for specifi cally inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-depend ent kinases, including cancer, viral infections (e.g., HIV) neurodegenerativ e disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. a therosclerosis). Moreover, certain members of this class are particularly us eful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.

Journal article

JOGALEKAR ASHUTOSH S, SNYDER JAMES P, LIOTTA DENNIS C, BARRETT ANTHONY G M, COOMBES RCDS, ALI SIMAK, SIWICKA ALEKSANDRA, BRACKOW JAN, SCHEIPER BODOet al., 2008, SELECTIVE INHIBITORS FOR CYCLIN-DEPENDENT KINASES

Journal article

BARRETT ANTHONY G M, SCHEIPER BODO, SNYDER JAMES P, COOMBES RCDS, SIWICKA ALEKSANDRA, ALI SIMAK, JOGALEKAR ASHUTOSH S, BRACKOW JAN, LIOTTA DENNIS Cet al., 2008, Selective inhibitors for cyclin-dependent kinases

Journal article

JOGALEKAR ASHUTOSH S, SNYDER JAMES P, LIOTTA DENNIS C, BARRETT ANTHONY GM, COOMBES RCDS, ALI SIMAK, SIWICKA ALEKSANDRA, BRACKOW JAN, SCHEIPER BODOet al., 2008, SELECTIVE INHIBITORS FOR CYCLIN-DEPENDENT KINASES

This invention provides a class of compounds which are useful for specifically inhibiting cyclin-dependent kinases. This class of compounds finds use in treating diseases resulting from inappropriate activity of cyclin-dependent kinases, including cancer, viral infections (e.g., HIV) neurodegenerative disorders (e.g. Alzheimer's disease), and cardiovascular disorders (e.g. atherosclerosis). Moreover, certain members of this class are particularly useful for inhibiting cyclin-dependent kinase 7 and are especially useful for the treatment of breast cancer.

Journal article

Tolhurst RS, Thomas RS, Kyle FJ, Patel H, Periyasamy M, Photiou A, Thiruchelvam PT, Lai CF, Al-sabbagh M, Fisher RA, Barry S, Crnogorac-Jurcevic T, Martin LA, Dowsett M, Coombes RC, Kamalati T, Ali Set al., Transient over-expression of estrogen receptor-alpha in breast cancer cells promotes cell survival and estrogen-independent growth, Breast Cancer Res. Treat.

Estrogen receptor-alpha (ERalpha) positive breast cancer frequently responds to inhibitors of ERalpha activity, such as tamoxifen, and/or to aromatase inhibitors that block estrogen biosynthesis. However, many patients become resistant to these agents through mechanisms that remain unclear. Previous studies have shown that expression of ERalpha in ERalpha-negative breast cancer cell lines frequently inhibits their growth. In order to determine the consequence of ERalpha over-expression in ERalpha-positive breast cancer cells, we over-expressed ERalpha in the MCF-7 breast cancer cell line using adenovirus gene transduction. ERalpha over-expression led to ligand-independent expression of the estrogen-regulated genes pS2 and PR and growth in the absence of estrogen. Interestingly, prolonged culturing of these cells in estrogen-free conditions led to the outgrowth of cells capable of growth in cultures from ERalpha transduced, but not in control cultures. From these cultures a line, MLET5, was established which remained ERalpha-positive, but grew in an estrogen-independent manner. Moreover, MLET5 cells were inhibited by anti-estrogens showing that ERalpha remains important for their growth. Gene expression microarray analysis comparing MCF-7 cells with MLET5 highlighted apoptosis as a major functional grouping that is altered in MLET5 cells, such that cell survival would be favoured. This conclusion was further substantiated by the demonstration that MLET5 show resistance to etoposide-induced apoptosis. As the gene expression microarray analysis also shows that the apoptosis gene set differentially expressed in MLET5 is enriched for estrogen-regulated genes, our findings suggest that transient over-expression of ERalpha could lead to increased cell survival and the development of estrogen-independent growth, thereby contributing to resistance to endocrine therapies in breast cancer patients.

Journal article

Thomas RS, Sarwar N, Phoenix F, Coombes RC, Ali Set al., 2008, Phosphorylation at serines 104 and 106 by Erk1/2 MAPK is important for estrogen receptor-α activity, Journal of Molecular Endocrinology, Vol: 40, Pages: 173-184, ISSN: 1479-6813

Phosphorylation of estrogen receptor-α (ERα) at specific residues in transcription activation function 1 (AF-1) can stimulate ERα activity in a ligand-independent manner. This has led to the proposal that AF-1 phosphorylation and the consequent increase in ERα activity could contribute to resistance to endocrine therapies in breast cancer patients. Previous studies have shown that serine 118 (S118) in AF-1 is phosphorylated by extracellular signal-regulated kinases 1 and 2 (Erk1/2) mitogen-activated protein kinase (MAPK) in a ligand-independent manner. Here, we show that serines 104 (S104) and 106 (S106) are also phosphorylated by MAPK in vitro and upon stimulation of MAPK activity in vivo. Phosphorylation of S104 and S106 can be inhibited by the MAP-erk kinase (MEK)1/2 inhibitor U0126 and by expression of kinase-dead Raf1. Further, we show that, although S118 is important for the stimulation of ERα activity by the selective ER modulator 4-hydroxytamoxifen (OHT), S104 and S106 are also required for the agonist activity of OHT. Acidic amino acid substitution of S104 or S106 stimulates ERα activity to a greater extent than the equivalent substitution at S118, suggesting that phosphorylation at S104 and S106 is important for ERα activity. Collectively, these data indicate that the MAPK stimulation of ERα activity involves the phosphorylation not only of S118 but also of S104 and S106, and that MAPK-mediated hyperphosphorylation of ERα at these sites may contribute to resistance to tamoxifen in breast cancer.

Journal article

Jiang J, Sarwar N, Peston D, Kulinskaya E, Shousha S, Coombes RC, Ali Set al., 2007, Phosphorylation of estrogen receptor-alpha at Ser(167) is indicative of longer disease-free and overall survival in breast cancer patients, CLINICAL CANCER RESEARCH, Vol: 13, Pages: 5769-5776, ISSN: 1078-0432

Journal article

PUFONG BORIS TUMI, ALI SIMAK, BULUWELA LAKI, KANDA PATRICK, VAINIKKA SATU, HART STEPHEN, JENKINSON JOHN DAVID, PORTER ANDREW CHRISTOPHER GEORet al., 2007, CONTROL OF GENE EXPRESSION USING A COMPLEX OF AN OLIGONUCLEOTIDE AND A REGULATORY PEPTIDE, WO03033701

Patent

Lopez-Garcia J, Periyasamy M, Thomas RS, Christian M, Leao M, Jat P, Kindle KB, Heery DM, Parker MG, Buluwela L, Kamalati T, Ali Set al., 2006, ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases, Nucleic Acids Research, Vol: 34, Pages: 6126-6136, ISSN: 1362-4962

The regulation of gene expression by estrogen receptor-α (ERα) requires the coordinated and temporal recruitment of diverse sets of transcriptional co-regulator complexes, which mediate nucleosome remodelling and histone modification. Using ERα as bait in a yeast two-hybrid screen, we have identified a novel ERα-interacting protein, ZNF366, which is a potent corepressor of ERα activity. The interaction between ZNF366 and ERα has been confirmed in vitro and in vivo, and is mediated by the zinc finger domains of the two proteins. Further, we show that ZNF366 acts as a corepressor by interacting with other known ERα corepressors, namely RIP140 and CtBP, to inhibit expression of estrogen-responsive genes in vivo. Together, our results indicate that ZNF366 may play an important role in regulating the expression of genes in response to estrogen.

Journal article

Sarwar N, Kim J-S, Jiang J, Peston D, Sinnett HD, Madden P, Gee JM, Nicholson RI, Lykkesfeldt AE, Shousha S, Coombes RC, Ali Set al., 2006, Phosphorylation of ER alpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ER alpha phosphorylation in breast cancer progression, ENDOCRINE-RELATED CANCER, Vol: 13, Pages: 851-861, ISSN: 1351-0088

Journal article

Martin LA, Farmer I, Johnston SRD, Ali S, Dowsett Met al., 2005, Elevated ERK1/ERK2/estrogen receptor cross-talk enhances estrogen-mediated signaling during long-term estrogen deprivation, 1st Tenovus/AstraZeneca Workshop on Therapeutic Resistance in Breat Cancer - Impact of Growth Factor Signalling Pathways and Implications for Future Treatment, Publisher: BIOSCIENTIFICA LTD, Pages: S75-S84, ISSN: 1351-0088

Conference paper

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